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Immunity. 2011 Apr 22;34(4):479-91. doi: 10.1016/j.immuni.2011.02.017. Epub 2011 Mar 31.

Structure of a domain-swapped FOXP3 dimer on DNA and its function in regulatory T cells.

Author information

1
Immune Disease Institute and Program in Cellular and Molecular Medicine, Children's Hospital, Boston, MA 02115, USA.

Erratum in

  • Immunity. 2011 Apr 22;34(4):627.

Abstract

The transcription factor FOXP3 is essential for the suppressive function of regulatory T cells that are required for maintaining self-tolerance. We have solved the crystal structure of the FOXP3 forkhead domain as a ternary complex with the DNA-binding domain of the transcription factor NFAT1 and a DNA oligonucleotide from the interleukin-2 promoter. A striking feature of this structure is that FOXP3 forms a domain-swapped dimer that bridges two molecules of DNA. Structure-guided or autoimmune disease (IPEX)-associated mutations in the domain-swap interface diminished dimer formation by the FOXP3 forkhead domain without compromising FOXP3 DNA binding. These mutations also eliminated T cell-suppressive activity conferred by FOXP3, both in vitro and in a murine model of autoimmune diabetes in vivo. We conclude that FOXP3-mediated suppressor function requires dimerization through the forkhead domain and that mutations in the dimer interface can lead to the systemic autoimmunity observed in IPEX patients.

PMID:
21458306
PMCID:
PMC3085397
DOI:
10.1016/j.immuni.2011.02.017
[Indexed for MEDLINE]
Free PMC Article

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